rs191722579

chr2-151529281-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001164507.2(NEB):c.21664T>A(p.Ser7222Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000255 in 1,613,420 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S7222S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: NEB NM_001164507.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.56

Genes affected

NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]

RIF1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10117504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NEB	NM_001164507.2	c.21664T>A	p.Ser7222Thr	missense_variant	146/182	ENST00000427231.7
NEB	NM_001164508.2	c.21664T>A	p.Ser7222Thr	missense_variant	146/182	ENST00000397345.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NEB	ENST00000397345.8	c.21664T>A	p.Ser7222Thr	missense_variant	146/182	5	NM_001164508.2	P5
NEB	ENST00000427231.7	c.21664T>A	p.Ser7222Thr	missense_variant	146/182	5	NM_001164507.2	A2

Frequencies

GnomAD3 genomes AF: 0.000224 AC: 34 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000209 AC: 52 AN: 249114 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135142

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000259 AC: 378 AN: 1461182 Hom.: 0 Cov.: 30 AF XY: 0.000253 AC XY: 184 AN XY: 726928

Gnomad4 AFR exome AF: 0.000149

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000393

Gnomad4 NFE exome AF: 0.000301

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000223 AC: 34 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74442

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000589

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000223 Hom.: 0

Bravo AF: 0.000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000174 AC: 21

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 19, 2023	- -

Nemaline myopathy 2 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 17, 2020	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2021

The c.16561T>A (p.S5521T) alteration is located in exon 119 (coding exon 117) of the NEB gene. This alteration results from a T to A substitution at nucleotide position 16561, causing the serine (S) at amino acid position 5521 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	21
Dann	Benign	0.97
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T;D;T;D;T;T;.;.
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.10	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;.;.;L;.;.;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.98	N;N;.;N;N;N;.;.
REVEL	Benign	0.11
Sift	Benign	0.36	T;T;.;T;T;T;.;.
Sift4G	Uncertain	0.016	D;D;D;D;D;T;D;D
Polyphen		0.97	.;.;.;.;D;.;.;.
Vest4		0.56
MVP		0.47
MPC		0.31
ClinPred		0.081	T
GERP RS		5.8
Varity_R		0.15
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs191722579; hg19: chr2-152385795;